2.1 Core Binding Factor Acute Myeloid Leukemia

2.2 Cytogenetically Normal Acute Myeloid Leukemia

Changes in the FLT3 gene are involved in a form of blood cancer known as cytogenetically normal acute myeloid leukemia (CN-AML). While large chromosomal abnormalities can be involved in the development of acute myeloid leukemia, about half of cases do not have these abnormalities; these are classified as CN-AML.

The FLT3 gene mutations involved in CN-AML are called somatic mutations; they are found only in cells that become cancerous and are not inherited. Two types of FLT3 gene mutations are found in CN-AML. The most common, which occurs in up to 34 percent of CN-AML cases, is called the FLT3 internal tandem duplication (FLT3-ITD). In this type of mutation, a short sequence of DNA is copied and inserted directly following the original sequence. The duplicated DNA sequence can vary in size, but all FLT3-ITD mutations result in alterations in the region of the protein that spans the cell membrane, known as the juxtamembrane domain. The altered juxtamembrane domain allows the FLT3 receptor to activate signaling pathways without binding of FL; the receptor is always turned on and is said to be constitutively activated. Constant signaling leads to uncontrolled proliferation of abnormal, immature white blood cells, a hallmark of acute myeloid leukemia.

The other type of FLT3 gene mutation is found in about 14 percent of people with CN-AML. These mutations are referred to as FLT3-TKD mutations because they change single protein building blocks (amino acids) in a region of the protein known as the tyrosine kinase domain (TKD). The most commonly changed amino acid is asparagine at position 835; it is typically replaced by the amino acid tyrosine. This mutation is written as Asp835Tyr or D835Y. Like FLT3-ITD mutations, FLT3-TKD mutations result in a constitutively activated FLT3 receptor and constant signaling, leading to acute myeloid leukemia.